JPH0735365B2 - Calcipher derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides the formula in the 25R or 25S epimeric form or mixtures thereof. Wherein R is hydrogen and the dotted line in the side chain is any additional C—C bond, or R is methyl and the dotted line in the side chain is the additional C—C bond, The present invention relates to a method for producing the calcipherol derivative.

The present invention also relates to the formula in the 25R or 25S epimeric form or a mixture thereof. Wherein R is hydrogen or methyl, to novel compounds, pharmaceutical compositions containing compounds of formula I or IA, and novel intermediates resulting in the preparation of these compounds.

The term "lower alkyl" as used herein preferably represents a straight or branched chain saturated hydrocarbon group containing 1 to 6 carbon atoms, such as methyl, ethyl, propyl,
Represents isopropyl, butyl, t-butyl, pentyl or hexyl. The term “C _3-6 alkylene” refers to straight or branched chain organic groups derived from unsaturated aliphatic hydrocarbon groups such as propylene or butylene. The term “aryl” refers to phenyl, or C _1-6.
It represents a phenyl having one or more substituents selected from alkyl and C _{1 to 6} alkoxy.

The process for preparing the compounds of formula I is of the formula Where R and the dotted line in the side chain have the meanings given above and R ¹ and R ² are hydrogen, lower alkyl or aryl, or taken together are C _3-6 alkylene. Formula a particular epimer Wherein R ³ is lower alkyl or aryl, and a compound obtained by reacting with Wherein R, R ¹ , R ² , R ³ and the dotted line on the side chain have the meanings given above, consisting of treating the compound with a deprotecting agent. Ketone II
The reaction of phosphine oxide III with phosphine oxide III is carried out in the presence of a base in a common ether solvent such as tetrahydrofuran (THF) or dioxane under an inert atmosphere such as argon at a temperature of about -80 to -50 ° C. Can be done in a range. Examples of suitable bases are alkyllithium compounds, such as n-butyllithium, and alkali metal dialkyl, or dialkylamides. The compound of formula IV can be purified by elution chromatography, for example on silica gel.

The compound of formula IV can be added to the corresponding compound of formula I after treatment with a deprotecting agent such as an alkanol, eg ethanol, or water in the presence of acid. Although any inorganic or lower alkanoic acid or sulfonic acid can be used, it is preferred to use the cation exchange resin as a suspension in the lower alkanol. The corresponding compound of formula I can be isolated by removal of the solid cation exchange resin by filtration and evaporation of the volatile constituents under reduced pressure.

The starting ketone of Formula II where R is hydrogen can be prepared as shown in Scheme 1 below, where R ¹ , R ² and R ³ are as described above.

The compound of formula V can be reduced with lithium aluminum hydride (LiAlH ₄ ) at 0 ° C. in a common anhydrous ether solvent such as THF to form the corresponding diol VI. Conversion of the diol VI to the corresponding triol VII can be carried out by removing protecting groups such as t-butyl-dimethylsilyl group with a 48% hydrofluoric acid solution in a mixture of acetonitrile and THF. it can.

Protection of the side chain vicinal diol in the compound of formula VII by conversion to acetonide VIII can be effected, for example, by treatment with 2,2-dimethoxypropane and catalysis with, for example, p-toluenesulfonic acid. Formula of the resulting compound of Formula VIII
The conversion of IX to the dihydro analog can be carried out by hydrogen conversion in a solvent such as ethyl acetate at atmospheric pressure over a 10% palladium on carbon catalyst. Finally, the corresponding ketone II can be obtained by oxidizing a compound of formula VIII or IX with, for example, 2,2-bipyridinium chlorochromate in a solvent such as methylene chloride and in the presence of anhydrous sodium acetate.

The starting ketone of formula II where R is methyl can be prepared as shown in Scheme 2 below. Where R ¹ and R ² are as described above and Ts is a p-toluenesulfonyl group.

The compound of formula X can be heated to 140 ° C. in a common anhydrous aromatic solvent such as xylene with, for example, mesaconic acid to form the isoxazolidine ester XI. The conversion of the diester to the corresponding diol X II is carried out in a conventional anhydrous ether solvent such as THF at ice bath temperature with LiAlH ₄
Can be used for reduction. Expression X
The ring opening of the isoxazolidine ring to form the compound of III is, for example, by N-methylation with methyl iodide in toluene at 60 ° C. and then reduction with zinc dust in acetic acid at room temperature, for example. It can be carried out. Alternatively,
This reduction can be done with LiAlH ₄ in THF.
Adjacent diols and protection on the side chains of compounds of formula XIII by conversion to acetonides XIV can be done as described above for compounds of formula VII. Conversion of a compound of formula XIV to a compound of formula XV is methylated with methyl iodide in dry toluene at 65 ° C in the presence of potassium carbonate,
This can then be done for example by removal with potassium t-butyrate at 55 ° C and finally at 100 ° C. The compound of formula XV is then converted to the tosylate XVI by p-toluenesulfonyl chloride in methylene chloride, for example in the presence of triethylamine. The reduction of a compound of formula X VI to a compound of formula X VII is accomplished by adding LiAl in THF at reflux temperature.
It can be done with H ₄ . Finally, the ketone II can be obtained, for example, by oxidation of a compound of formula XVII as described above for a compound of formula VIII or IX.

The compounds of formula I have anti-proliferative and differentiation-inducing activity.
And therefore diffuse tumors in warm-blooded animals (diffuse
tumor, eg leukemias, eg monocytic leukemia and promyelocytic leukemia, and solid tumors, eg lung carcinomas, melanoma, pigmented rectum. Cancer (colorectal carcinoma) and breast tumor (breast t)
umors) are useful drugs. The antiproliferative and differentiation-inducing activity of the compounds of formula I can be determined by known methods, for example, Progress in Quantum Research and Chierapy, Vol. Raven Press, New York, 1982 (Progress in Canc
er Research and Therapy, Vol.23: Maturation Factors
and Cancer, Ed. MASMoore, Raven Press, NY1982); It can be demonstrated using the methods described in Nature 270 (1977) 347-9 and Blood 54 (1979) 429-39.

The results obtained with the following compounds of formula I are shown in Tables 1 to 4: 1α, 25 (S), 26-trihydroxycholecalciferol [1α, 25S, 26- (OH) ₃ D ₃ 1α, 25 (R), 26-trihydroxycholecalciferol [1α, 25R, 26- (OH) ₃ D ₃ ] 1α, 25 (S), 26-trihydroxy-Δ ²² -cholecalciferol [ 1α, 25S, 26- (OH) ₃ -Δ ²² -D ₃ ] 1α, 25 (S), 26-trihydroxyergocalciferol [1α, 25S, 26- (OH) ₃ -D ₂ ].

The R and S epimers of Formula I can be administered to warm-blooded animals in need of treatment of tumor cells in dosages ranging from 0.05 to 500 μg / Kg / day. The compounds are administered prophylactically as well as intramuscularly, intravenously or intraperitoneally, for example in the form of tablets, capsules, syrups or elixirs for prophylactic administration, or as a sterile solution or suspension for non-progressive administration. be able to. R or S epimer of formula I about 0.05-500
A pharmaceutically acceptable excipient (ve
hicle), a carrier, an excipient such as dicalcium phosphate; a binder such as tragacanth gum; a preservative or stabilizer. Tablets and capsules may also include disintegrants such as corn starch; lubricants such as magnesium stearate; sweeteners such as sucrose; and flavoring agents such as peppermint. Various other materials, such as coatings, eg shellac, may be present to improve the physical form of the dosage unit. Sterile injectable compositions can include water, naturally occurring vegetable oils such as sesame oil, or synthetic fat excipients such as ethyl oleate. Further, a buffering agent, a preservative and an antioxidant can be added.

The following examples further illustrate the present invention. All temperatures are in degrees Celsius.

Reference Example 1 A) A suspension of 0.122 g of LiAlH _{4 in} 3.2 ml of dry THF at 0 ° C. [1R- [1β- (R *, E, S *), 30αα, 4β, 7aβ]]-
6- [Octahydro-4- (1,1-dimethylethyl) dimethylsilyloxy-7a-methyl-1H-indene-1-
Yl] -2-hydroxy-2-methyl-4-heptenecarboxylic acid methyl ester 0.336 g and dry THF 4 ml were added. After 1 hour, 0.061 g of LiAlH ₄ was added, the mixture was stirred for 20 minutes and then the cooling bath was removed. After 2.5 hours, the mixture is reduced to 0
It was cooled to ° C and 0.6 ml of ethyl acetate was added. After stirring, 3.5 ml of saturated ammonium chloride solution was added, the cooling bath was removed,
The mixture was stirred, then filtered and washed with chloroform and ethyl acetate. The liquor was dried, passed and concentrated. The residue was chromatographed on silica gel with hexane-ethyl acetate to give [1R- [1β- (R
*, E, S *), 3aα, 4β, 7aβ]]-6- [octahydro-
4-[(1,1-Dimethylethyl) -dimethylsilyloxy-7α-methyl-1H-inden-1-yl] -2-methyl-4-heptene-1,2-diol (yield 89%) was obtained. In addition, ▲ [α] ²⁵ _D ▼ = + 48.75 ° (c0.9388, chloroform).

B) To a solution of 0.257 g of the silyl ether obtained in A) above, 3.6 ml of acetonitrile and 3.0 ml of THF was added 2.8 ml of 48% aqueous hydrogen fluoride under argon. The mixture was stirred for 3 hours and then poured into 200 ml chloroform and 20 ml water. The aqueous phase was extracted with 2 × 100 ml of chloroform, and the combined chloroform layers were washed with 20 ml of saturated sodium hydrogen carbonate solution. The extract was dried, filtered, and concentrated. The residue was chromatographed on silica gel with ethyl acetate to give [1R- [1β- (R *, E, S *), 3aα, 4β, 7a
β]]-6-Octahydro-4-hydroxy-7a-methyl-1H-inden-1-yl) -2-methyl-4-heptene-1,2-diol (0.176 g, 95%) was obtained, mp 87 ~ 8
8 ° C (methanol-water, 1: 1), ▲ [α] ²⁵ _D ▼ + 28.2 ° (c0.748 chloroform).

C) A solution of 0.254 g of the triol obtained in B) above, 10 ml of 2,2-dimethoxypropane and 16 ml of p-toluenesulfonic acid was stirred for 50 minutes under argon. Then 2m methanol
l was added and the mixture was stirred for 45 minutes, then 2.5 ml of saturated sodium hydrogen carbonate solution was added. The mixture was stirred for 1 hour, diluted with 150 ml chloroform and washed with 10 ml water.
The aqueous phase was extracted with 2 × 50 ml of chloroform, and the combined chloroform layers were dried. The mixture is passed, concentrated and chromatographed on silica gel with hexane-ethyl acetate to give [1R- [1β- (R *, E, S *), 3aα, 4
β, 7aβ]]-Octahydro-7a-methyl-1- [1-
Methyl-4- (2,2,4-trimethyl-1,3-dioxolan-4-yl) -butenyl] -1H-inden-4-ol
0.259 g (90%) was obtained, ▲ [α] ²⁵ _D ▼ + 21.27 ° (c0.6
018, chloroform).

D) The butene derivative obtained in C) above was hydrogenated under atmospheric pressure over 10% palladium on carbon in ethyl acetate. The solvent was removed, and quantitatively amorphous [1R- [1β (R *, S *), 3aα, 4β, 7aα]]-octahydro-7a-methyl-1- [1-methyl-4] was obtained. − (2,2,4
-Trimethyl-1,3-dioxolan-4-yl) -butyl] -1H-inden-4-ol was obtained, ▲ [α] ²⁵ _D
▼ + 33.3 ° (c0.941, chloroform).

E) To a suspension of 1.72 g of 2,2'-bipyridinium chlorochromate and 0.860 g of anhydrous sodium acetate in 10 ml of methylene chloride is added a solution of 0.500 g of the indenol derivative obtained in D) in 5 ml of methylene chloride. The mixture was stirred for 2 hours. Furthermore, 2,2-bipyridinium chlorochromate 0.8
00g was added and stirring was continued for 2.5 hours. 2-propanol 1m
l was added and after 15 minutes the mixture was diluted with water and extracted with ether. The combined organic phases are dried, evaporated and the residue is purified over silica gel with hexane-ethyl acetate to give pure [1R- [1R *, S *)-1β, 3aα, 7a
β] -octahydro-7a-methyl-1- [1-methyl-
4- (2,2,4-trimethyl-1,3-dioxolan-4-yl) butyl] -4H-inden-4-one 0.446 g (yield 90
%) Was obtained.

F) [3S- (3α, 5β, Z)]-2- in 30 ml of anhydrous THF
[2-methylene-3,5-bis [(1,1-dimethylethyl)
Dimethylsilyloxy] cyclohexylidene] ethyldiphenylphosphine oxide 1.430 g solution at −78 ° C. under argon at −78 ° C. in a 1.7 M solution of n-butyllithium in hexane.
The solution was treated dropwise with 1.4 ml. After 5 minutes, a solution of 0.460 g of the indenone derivative obtained in E) in 5 ml of anhydrous THF was added dropwise and the mixture was stirred at -78 ° C for 2.5 hours, then 1 of sodium bicarbonate.
It was treated with 5 ml of N aqueous solution and potassium sodium tartrate, brought to room temperature, and extracted with ethyl acetate. The impregnated organic extract is dried and evaporated and the residue is extracted on silica gel with hexane-
Chromatography with ethyl acetate gave pure 1α, 25S, 26-trihydroxy-cholecalciferol-1,3-dimethyl-t-butylsilyl 25,26-acetonide.
Obtained 0.91 g (95%).

G) Acetonide obtained in F) in 200 ml of methanol 0.9
To 1 g of solution was added 45 g of cation exchange resin and the mixture was stirred under argon for 16 hours. After filtration, the methanol solution was evaporated to dryness, the residue was dissolved in 100 ml of ethyl acetate and washed with brine. The organic phases are combined, dried, evaporated and the residue is purified by chromatography on silica gel with ethyl acetate and 0.486 g of 1α, 25S, 26-trihydroxycholecalciferol (yield 86%), melting point
163-164 ° C, ▲ [α] ²⁵ _D ▼ + 58.8 ° (c0.5, methanol).

Example 1 A) In the same manner as in Reference Example 1E), 0.145 g of the indenol derivative obtained in Reference Example 1C) was converted into pure [1R
-(1R *, 2E, S *) 1β, 3aα, 7aβ] -Octahydro-7
a-Methyl-1- [1-methyl-4- (2,2,4-trimethyl-1,3-dioxolan-4-yl) -2-butenyl]
-4H-inden-4-one 0.134 g (93%) was obtained, ▲
[Α] ²⁵ _D ▼ + 6.79 ° (c0.2, ethanol).

B) In the same manner as in Reference Examples 1F) and G), [3S-
(3α, 5β, Z)]-2- [2-Methylene-3,5-bis [(1,1-dimethylethyl) dimethylsilyloxy] cyclohexylidene] ethyldiphenylphosphine oxide 0.354 g and Example 1A ) Indenone derivative obtained in).
Starting from 113 g, 0.131 g (90%) of pure 1α, 25S, 26-trihydroxy-Δ ²² -cholecalciferol was obtained, ▲ [α] ²⁵ _D ▼ + 44.9 (c0.2, ethanol).

Example 2 A) [1R [1α (R *, Z), 3aβ, 4α, 7aα]]-octahydro-7a-methyl-1- [1-methyl-3-methylimino) propyl] -1H-indene-4- All-N-oxide 7.60 g (30 mmol), methyl mesaconate 5.70 g
A mixture of (36 mmol) and 4 ml of xylene was heated to 140 ° C. The resulting solution was heated for 1 hour and then cooled to room temperature. Chromatography on silica gel with CH ₂ Cl ₂ / EtOAc to give [3S, 4S, 5S [3β, 4α, 5β [[(2R
*), 1R * (1β, 3aα, 4β, 7aβ)]]]-3- [2-
(Octahydro-4-hydroxy-7a-methyl-1H-inden-1-yl) -propyl] -2,2-dimethyl-4,5
-Isoxazolidinecarboxylic acid dimethyl ester 5.42 g
(44%) was obtained, ▲ [α] ²⁵ _D ▼ = + 126.4 ° (c0.911,
CHCl ₃ ); m / e 411.

B) The diester obtained in A) above in 30 ml of dry THF 10.
A solution of 53 g (25.6 mmol) of dry THF150 kept under argon at a temperature between 3 and 8 ° C for 30 minutes.
LiAlH ₄ 4.85 g (129 mmol) in ml was added dropwise to a stirred suspension. The suspension is stirred for 1 hour, then 6 ml of water,
Subsequently, 4 ml of 1N NaOH was added. After 15 minutes the suspension was passed.
The filter cake was washed with THF 6 x 25 ml. When the solvent was evaporated from the combined liquid, 8.32 g of a solid residue was obtained. The filter cake still contained the product, which was added to 250 ml of 20% Rochelle salt solution, stirred for 1 hour and extracted with 3 × 150 ml of ethyl acetate. The combined organic phases were dried, filtered and evaporated to give a residue 0.70 g. Thus, crude [3R, 4R, 5S [3β, 4α, 5β] [(2R *),
(1β, 3aα, 4β, 7aβ)]]-3- [2- (Octahydro-4-hydroxy-7a-methyl-1H-indene-1
The total amount of -yl) propyl] -2,2-dimethyl-4,5-isoxazolidimethanol was 9.02 g (99%). Melting point 1
51-152 ° C (EtOAc), ▲ [α] ²⁵ _D ▼ ＝ ＋ 108.4 ° (c0.9
_{44, CHCl 3), m /} e355.

C) A solution of the dimethanol derivative obtained in B) above and 2.5 ml (38 mmol) of methyl iodide in 10 ml of dry THF and 50 ml of toluene was heated to 60 ° C. for 3.5 hours and then evaporated to dryness. The crude methiodide was dissolved in 250 ml of 50% aqueous acetic acid with warming and stirring. After cooling this solution to room temperature, 9.0 g (137 mmol) of zinc powder was added. The suspension was stirred overnight to remove residual zinc by filtration,
Wash with aqueous HOAc. The pH of the liquid was adjusted to 11 with 230 ml of concentrated ammonium hydroxide. CH ₂ Cl ₂ 3 × 300 ml, ether 2
Extracted with 300 mL of CH ₂ Cl ₂ / i-PrOH ₂ × 250 mL, and crude [1R- [1α (3R *, 4S *, 5R *, 6S *), 3aβ, 4α, 7a
α] -6-Octahydro-4-hydroxy-7a-methyl-H-inden-1-yl) -4- (dimethylamino)
-3-Hydroxymethyl-2-methylheptane-1,2-
8.7 g of diol was obtained.

Recrystallization from CH ₂ Cl ₂ gave 5.90 g of crystals. From mother liquor,
After chromatography on silica gel with EtOAc MeOH / Et ₃ N, 1.62 g was obtained, the total product being 7.52 g.
(Yield 81%), melting point 178-180 ° C (CH ₂ Cl ₂ ) ▲
[Α] ²⁵ _D ▼ = + 21.7 ° (c0.986, CHCl ₃ ).

D) A solution of 3.0 g (15.8 mmol) of p-toluenesulfonic acid monohydrate in a suspension of 4.90 g (13.2 mmol) of the diol obtained in C) above in 75 ml of acetone and 4.9 ml of dimethoxypropane. Was generated and the solution was stirred under argon for 17 hours. Then 8 ml of 2N NaOH was added and the mixture was concentrated. The remaining aqueous suspension was washed with methylene chloride 4 x 10
It was extracted with 0 ml. The combined organic phases were dried, filtered and evaporated to give 5.7 g of product. Hexane / E on silica gel
Purified by intermediate pressure liquid chromatography using tOAc / Et ₃ N, [1R- [1α (1R *, 3S *, 4R *) [4S
*], 3aβ, 4α, 7aα]]-Octahydro-7a-methyl-
1- [3- (dimethylamino) -4-hydroxymethyl-1-methyl-4- (2,2,4-trimethyl-1,3-dioxolan-4-yl) -butyl] -1H-indene-4- Obtained all 4.79 g (88%), melting point 104-105 ° C (pentane / ether, 2: 1), ▲ [α] ²⁵ _D ▼ ＝ + 19.5 ° (c0.94
3, CHCl ₃ ).

E) A solution of the butylindenol derivative obtained in D) above and 0.5 ml (7.5 mmol) of methyl iodide in 20 ml of dry toluene and 50 mg of anhydrous potassium carbonate were heated to 65 ° C. for 16 hours under argon. Furthermore, 0.5 ml of methyl iodide (7.5
Mmol) and heating continued for 4.5 hours. The reaction mixture was evaporated. To the obtained residue were added 10 ml of t-butanol and 1.12 g (10 mmol) of potassium t-butyrate. The reaction mixture was heated to 55 ° C under argon for 24 hours,
Then heated at reflux for 5 hours. The t-butanol was evaporated. 10 ml of water was added to the residue. This is ether 3 ×
Extracted with 50 ml. The combined extracts were dried, filtered and evaporated to give 1.63 g of crude product. CH ₂ on silica gel
It was subjected to intermediate pressure liquid chromatography using Cl ₂ / EtOAc to give [1R- [1α (1R *, E, 4R *), [4S *], 3aβ, 4
α, 7aα]]-Octahydro-7a-methyl-1- [4-
(Hydroxymethyl) -1-methyl-4-[(2,2,4-
881 mg of trimethyl-1,3-dioxolan-4-yl) -2-butenyl] -1H-inden-4-ol was obtained.

F) 742 mg (2.0 mmol) of the indenol derivative obtained in E) above in 10 ml of methylene chloride and triethylamine
To a stirred solution of 613 mg (6.0 mmol) at 0 ° C. under argon was added a solution of 385 mg (2.0 mmol) of p-toluenesulfonyl chloride (TsCl) in 4 ml of methylene chloride. The bath was removed at 0 ° C. for 45 minutes. After 5 hours at room temperature, 204 mg (2 mmol) triethylamine and TsCl385
mg (2 mmol) was added. After 22 hours, triethylamine 204 mg and TsCl 385 mg were added. After 7 hours, the reaction mixture was poured into 10 ml of 1N NaOH. After phase separation, the aqueous phase was extracted with 2x20 ml methylene chloride. The extract was washed with 10 ml of 1N NaOH. The combined organic extracts were dried, filtered and evaporated to give 1.35 g of crude product. Separation by liquid chromatography on silica gel with hexane / EtOAc gives [1R- [1α (1R *, E, 4R *), [4S *], 3aβ, 4
α, 7aα]]-Octahydro-7a-methyl-1- [1-
Methyl-4-[[[4-methylphenyl) sulfonyl]
Oxy] methyl] -4-[[2,2,4-trimethyl-1,3-
840 mg (80%) of dioxolan-4-yl) -2-butenyl] -1H-inden-4-ol were obtained.

G) To a stirred suspension of 240 mg LiAlH _{4 in} 15 ml THF was added under argon a solution of 818 mg (1.57 mmol) tosylate obtained in F). The suspension was heated under reflux for 3 hours and then cooled to 0 ° C. 0.4 ml water, then 1N NaOH 0.
6 ml was added. The resulting mixture was stirred for 15 minutes and then passed. The filter cake was washed with 2 × 50 ml THF. When the combined solution was evaporated, 641 mg of crude product was obtained.
Chromatograph on silica gel with hexane / EtOAc to give [1R- [1α (1R *, E, 4S *), [4S *],
3aβ, 4α, 7aα]]-Octahydro-7a-methyl-1-
[1,4-dimethyl-4-[(2,2,4-trimethyl-1,3-
Dioxolan-4-yl) -2-butenyl] -1H-inden-4-ol 498 mg (90%) was obtained, mp 69-71 ° C.
(Hexane), ▲ [α] ²⁵ _D ▼ ＝ ＋ 5.18 (c1.023, CHC
l ₃ ).

H) In the same manner as in Reference Example 1E), 1.5 g (5.13 mmol) of 2,2′-dipyridinium chlorochromate and 0.300 g (0.86 mmol) of the indenol derivative obtained in Example 2G) were used to prepare [1R- [ 1β (1R *, 2E, 4S *], 3aα, 7a
β]]-Octahydro-7a-methyl-1- [1,4-dimethyl-4-[(2,2,4-trimethyl-1,3-dioxolan-4-yl) -2-butenyl] -4H-indene 0.2984 g (95%) of -4-one was obtained, ▲ [α] ²⁵ _D ▼ = -12.10 (c0.5, ethanol).

I) In the same manner as in Reference Examples 1F) and G), [3S-
(3α, 5β, Z)]-2- [2-methylene-3,5-bis [(1,1-dimethylethyl) dimethylsilyloxy] cyclohexylidene] ethyldiphenylphosphine oxide 665 mg (1.14 mmol) and From 234 mg (0.671 mmol) of the indenone derivative obtained in Example 2H), pure 1
α, 25S, 26-Trihydroxyergocalciferol 248
mg (83%) was obtained, melting point 186-187 ° C., ▲ [α] ²⁵ _D ▼ =
+40.2 (c0.3, ethanol): ¹ H NMR (200MHz, CD ₃ OD)
δ 0.58 (s, 3H), 0.98 (d, J = 7.2Hz, 3H) 1.06 (d, J = 7.
6Hz, 3H), 1.08 (s, 3H), 3.40 (AB q, JAB = 8.4Hz, △
γ = 16.0Hz, 2H), 4.14 (m, 1H), 4.34 (m, 1H), 4.90
(S, 1H), 5.26 (dd, J ₁ = 8.4Hz, J ₂ = 15.6Hz, 1H), 5.29
(S, 1H), 5.45 (dd, J ₁ = 7.9Hz, J ₂ = 15.6Hz) 1H), 6.
08 (d, J = 11.6Hz, 1H), 6.32 (d, J = 11.6Hz, 1H).

Example A Preparation of Injectable Dosage Form Ingredients: Amount / ml: Sodium chloride 1.5 mg Monobasic sodium phosphate 9.2 mg EDTA disodium salt 1.0 mg Isoascorbic acid 10.0 mg Tween 20 (hexitol anhydrous) Polyalkylene derivative of long-chain fatty acid ester) 4.0 mg 1α, 25S, 26- (OH) _3- △ ²² -D ₃ , 1α, 25S, 26- (OH) ₃ -D ₃ or 1α, 25S, 26- (OH) ₃ -D ₃ desired concentration Sodium hydroxide, sufficient quantity to bring pH value to 7.0 Water for injection, sufficient quantity Example B Preparation of oral dosage form mg / capsule 1α, 25S, 26 -(OH) _3- △ ²² -D ₃ , 1α, 25S, 26- (OH) ₃ -D ₃ or 1α, 25R, 26- (OH) ₃ -D ₃ Desired concentration Neobi (Neobee) M5 (intermediate) Chain triglyceride) 200.00 Butylated hydroxyanisole 0.01 Butylated hydroxytoluene 0.01

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Gary Arthur Toruitz, Pasaytsk Sutyuart Street, New Jersey, USA 38 (72) Inventor Milan Radsie Uskokovitsk, United States At Permont Clare Highland, Avenyu 253 ( 72) Inventor Peter Michael Uobklitsch, Natrey Rhoda Avenieu, New Jersey, USA 124 (56) Reference JP-A-58-210017 (JP, A)

Claims (9)

[Claims] 1. A formula as a 25R or 25S epimeric form or a mixture thereof. Wherein R is hydrogen or methyl. 2. The calcipherol derivative according to claim 1, wherein R is hydrogen. 3. 1α, 25 (S), 26-trihydroxy-Δ ²²
A compound according to claim 2 which is cholecalciferol. 4. The compound according to claim 1, which is 1α, 25 (S), 26-trihydroxy-ergocalciferol. 5. A 1α, 25 (S), 26-trihydroxy-22-
A compound according to claim 1 which is dehydrocholecalciferol. 6. A formula Wherein R is hydrogen or methyl, and R ¹ and R ² are hydrogen, lower alkyl or aryl, or taken together are C _3-6 -alkylene. Wherein R ³ is lower alkyl or aryl, and a compound obtained by reacting with Wherein R, R ¹ , R ² and R ³ have the meanings given above, wherein the compound is a 25R or 25S epimeric form or a mixture thereof, characterized in that the compound is treated with a deprotecting agent. In the formula, R has the above-mentioned meaning, A method for producing a calcipirol derivative according to 7. The method of claim 6 wherein R is hydrogen. 8. A process according to claim 6 or 7 for producing a 25 (S) -epimer of formula IA. 9. A formula as a 25R or 25S epimeric form or a compound thereof In the formula, R is hydrogen or methyl, and a calcipherol derivative of is contained as an active ingredient.